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Investigating human disease using stem cell models

Nature Reviews Genetics volume 15, pages 625–639 (2014)Cite this article

Subjects

This article has been updated

Key Points

  • Adult stem cells, especially human neural stem cells, have been derived from adult somatic tissue and successfully used to model diseases such as fragile X syndrome. However, the number of adult stem cell lines that can be efficiently derived and expanded in culture is severely limited.

  • Human embryonic stem cells (ESCs) are pluripotent and expandable, but they are derived from pre-implantation embryos. Although human ESCs have been derived from embryos carrying mutations that cause a range of different disorders, only a few diseases can be diagnosed using pre-implantation genetic diagnosis (PGD). In addition, research involving PGD and human ESCs is controversial and is illegal in some countries.

  • Induced pluripotent stem cells (iPSCs) can be generated from specific patients with known genotypes and observable phenotypes, and they are therefore ideally suited to disease modelling. iPSC-derived cells have been used to model Mendelian disorders, genetically complex diseases and infectious diseases.

  • Several studies have used genome editing to correct a disease-causing mutation in iPSCs and thereby show a causal relationship with a disease phenotype. More recently, studies have used gene-edited iPSCs to better understand the molecular mechanisms that underlie disease pathogenesis. Future studies could use genome editing as a tool to understand genetically complex disorders.

  • iPSC-based models are being used to identify new therapeutics, particularly new drug candidates, and to evaluate drug toxicity. Future work could use these models to stratify patients into drug-responsive and non-responsive groups.

  • A major challenge is to differentiate the required cell type from iPSCs for disease modelling. In addition, differentiated cells tend to be heterogeneous and immature.

Abstract

Tractable and accurate disease models are essential for understanding disease pathogenesis and for developing new therapeutics. As stem cells are capable of self-renewal and differentiation, they are ideally suited both for generating these models and for obtaining the large quantities of cells required for drug development and transplantation therapies. Although proof of principle for the use of adult stem cells and embryonic stem cells in disease modelling has been established, induced pluripotent stem cells (iPSCs) have demonstrated the greatest utility for modelling human diseases. Furthermore, combining gene editing with iPSCs enables the generation of models of genetically complex disorders.

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Figure 1: Generation and applications of patient-specific disease models.
Figure 2: Using stem cell disease models to evaluate the contribution of specific loci to complex polygenic disorders.

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Change history

  • 08 August 2014

    In this article, some unintentional mistakes occurred, primarily misnumbered citations. In Table 1, KCNH2 gene correction was incorrectly assigned to reference 86 instead of reference 115, LRRK2 phenotypes were incorrectly assigned to references 13, 14 and 16 instead of 26, 27 and 29, SMN1 gene correction was incorrectly assigned to reference 26 instead of 41, and the cardiomyocyte arrhythmia resulting from CACNA1C mutation (corrected from CACNA1B) was incorrectly assigned to reference 125 instead of 139. Additionally, in Box 3, some of the studies of dopaminergic neuron differentiation were incorrectly assigned to references 13 and 16 instead of 26 and 29. Finally, in the reference list the annotation highlighting work in which genetic correction of a mutation that causes a neurodegenerative disease in patients leads to a phenotypic reversion in vitro was incorrectly assigned to reference 12 instead of references 30, 39–41, 96–98, 123 and 132. The article has been corrected online. The authors apologize for these errors.

References

  1. Schwartz, P. H. et al. Neural progenitor cells from an adult patient with fragile X syndrome. BMC Med. Genet. 6, 2 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Haidet-Phillips, A. M. et al. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nature Biotech. 29, 824–828 (2011). In this study, neural progenitors were derived from a patient with ALS and differentiated into astrocytes that showed ALS-like neurotoxicity to co-cultured MNs.

    Article  CAS  Google Scholar 

  3. Eiges, R. et al. Developmental study of fragile X syndrome using human embryonic stem cells derived from preimplantation genetically diagnosed embryos. Cell Stem Cell 1, 568–577 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Niclis, J. C. et al. Characterization of forebrain neurons derived from late-onset Huntington's disease human embryonic stem cell lines. Front. Cell Neurosci. 7, 37 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Biancotti, J. C. et al. Human embryonic stem cells as models for aneuploid chromosomal syndromes. Stem Cells 28, 1530–1540 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Mateizel, I. et al. Derivation of human embryonic stem cell lines from embryos obtained after IVF and after PGD for monogenic disorders. Hum. Reprod. 21, 503–511 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Marchetto, M. C. et al. Non-cell-autonomous effect of human SOD1G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3, 649–657 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Di Giorgio, F. P., Boulting, G. L., Bobrowicz, S. & Eggan, K. C. Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 3, 637–648 (2008). References 7 and 8 show a non-cell-autonomous effect of ALS-causing mutations in astrocytes on human stem-cell-derived MNs.

    Article  CAS  PubMed  Google Scholar 

  9. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007). References 9 and 10 report the first generation of iPSCs from human somatic cells.

    Article  CAS  PubMed  Google Scholar 

  11. Ebert, A. D. et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457, 277–280 (2009). This study is the first to show patient-specific iPSC-derived cells with disease-associated phenotypes.

    Article  CAS  PubMed  Google Scholar 

  12. HD iPSC Consortium. Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell 11, 264–278 (2012).

    Article  CAS  Google Scholar 

  13. Zhang, N., An, M. C., Montoro, D. & Ellerby, L. M. Characterization of human Huntington's disease cell model from induced pluripotent stem cells. PLoS Curr. 2, RRN1193 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chae, J. I. et al. Quantitative proteomic analysis of induced pluripotent stem cells derived from a human Huntington's disease patient. Biochem. J. 446, 359–371 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Camnasio, S. et al. The first reported generation of several induced pluripotent stem cell lines from homozygous and heterozygous Huntington's disease patients demonstrates mutation related enhanced lysosomal activity. Neurobiol. Dis. 46, 41–51 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Jeon, I. et al. Neuronal properties, in vivo effects, and pathology of a Huntington's disease patient-derived induced pluripotent stem cells. Stem Cells 30, 2054–2062 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Moretti, A. et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N. Engl. J. Med. 363, 1397–1409 (2010). This is the first report of an in vitro model of a cardiac disease using human iPSCs.

    Article  CAS  PubMed  Google Scholar 

  18. Itzhaki, I. et al. Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471, 225–229 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Zhang, S. et al. Rescue of ATP7B function in hepatocyte-like cells from Wilson's disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin. Hum. Mol. Genet. 20, 3176–3187 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Eggenschwiler, R. et al. Sustained knockdown of a disease-causing gene in patient-specific induced pluripotent stem cells using lentiviral vector-based gene therapy. Stem Cells Transl. Med. 2, 641–654 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ye, Z. et al. Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders. Blood 114, 5473–5480 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim, J. et al. An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. Cell Rep. 3, 2088–2099 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, X. et al. Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson's disease mutation G2019S. J. Neurosci. 30, 1788–1797 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Healy, D. G. et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case–control study. Lancet Neurol. 7, 583–590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Trinh, J. et al. A comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism. Neurobiol. Aging 35, 1125–1131 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Nguyen, H. N. et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8, 267–280 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sanchez-Danes, A. et al. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Mol. Med. 4, 380–395 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kondo, T. et al. Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12, 487–496 (2013). This study uses iPSCs from patients with different forms of genetic and sporadic AD to model AD pathology, test potential treatments and show differential responsiveness of the different patient groups.

    Article  CAS  PubMed  Google Scholar 

  29. Reinhardt, P. et al. Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell 12, 354–367 (2013). This paper shows that genetic correction of a LRRK2 mutation modifies the in vitro phenotypes in midbrain DANs that are associated with PD, including aberrant MAPK signalling and gene transcription.

    Article  CAS  PubMed  Google Scholar 

  30. Liu, G. H. et al. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature 491, 603–607 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Miller, J. D. et al. Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13, 691–705 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dekker, P. et al. Chronic inhibition of the respiratory chain in human fibroblast cultures: differential responses related to subject chronological and biological age. J. Gerontol. A Biol. Sci. Med. Sci. 67, 456–464 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Noppe, G. et al. Rapid flow cytometric method for measuring senescence associated β-galactosidase activity in human fibroblasts. Cytometry A 75, 910–916 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Koch, P. et al. Excitation-induced ataxin-3 aggregation in neurons from patients with Machado–Joseph disease. Nature 480, 543–546 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Yusa, K. et al. Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells. Nature 478, 391–394 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Choi, S. M. et al. Efficient drug screening and gene correction for treating liver disease using patient-specific stem cells. Hepatology 57, 2458–2468 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zou, J., Mali, P., Huang, X., Dowey, S. N. & Cheng, L. Site-specific gene correction of a point mutation in human iPS cells derived from an adult patient with sickle cell disease. Blood 118, 4599–4608 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang, Y. et al. Genetic correction of beta-thalassemia patient-specific iPS cells and its use in improving hemoglobin production in irradiated SCID mice. Cell Res. 22, 637–648 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fong, H. et al. Genetic correction of tauopathy phenotypes in neurons derived from human induced pluripotent stem cells. Stem Cell Rep. 1, 226–234 (2013).

    Article  CAS  Google Scholar 

  40. An, M. C. et al. Genetic correction of Huntington's disease phenotypes in induced pluripotent stem cells. Cell Stem Cell 11, 253–263 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Corti, S. et al. Genetic correction of human induced pluripotent stem cells from patients with spinal muscular atrophy. Sci. Transl Med. 4, 165ra162 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. ISIS Pharmaceuticals. Press release: Data from ISIS-SMN Rx Phase 1 study in children with spinal muscular atrophy presented at the American Academy of Neurology Meeting [online], (2014).

  43. Ryan, S. D. et al. Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2–PGC1α transcription. Cell 155, 1351–1364 (2013). By using genetic targeting, this study shows that mutant SNCA leads to nitrosative stress, as well as to nitrosylation and thus inactivation of the neuroprotective MEF2–PGC-1α pathway. As nitrosative stress is a feature of many neurodegenerative diseases, this mechanism could apply to other disorders.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ding, Q. et al. A TALEN genome-editing system for generating human stem cell-based disease models. Cell Stem Cell 12, 238–251 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Roelandt, P. et al. Human pluripotent stem cell-derived hepatocytes support complete replication of hepatitis C virus. J. Hepatol 57, 246–251 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Wu, X. et al. Productive hepatitis C virus infection of stem cell-derived hepatocytes reveals a critical transition to viral permissiveness during differentiation. PLoS Pathog. 8, e1002617 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yoshida, T. et al. Use of human hepatocyte-like cells derived from induced pluripotent stem cells as a model for hepatocytes in hepatitis C virus infection. Biochem. Biophys. Res. Commun. 416, 119–124 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Schwartz, R. E. et al. Modeling hepatitis C virus infection using human induced pluripotent stem cells. Proc. Natl Acad. Sci. USA 109, 2544–2548 (2012).

    Article  PubMed  Google Scholar 

  49. Penkert, R. R. & Kalejta, R. F. Human embryonic stem cell lines model experimental human cytomegalovirus latency. MBio 4, e00298–00213 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. D'Aiuto, L. et al. Human induced pluripotent stem cell-derived models to investigate human cytomegalovirus infection in neural cells. PLoS ONE 7, e49700 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hoing, S. et al. Discovery of inhibitors of microglial neurotoxicity acting through multiple mechanisms using a stem-cell-based phenotypic assay. Cell Stem Cell 11, 620–632 (2012). This study shows the feasibility of high-throughput screening using a stem-cell-based phenotypic assay with a complex co-culture system that models ALS. Hit compounds that acted through multiple mechanisms were identified.

    Article  CAS  PubMed  Google Scholar 

  52. Yang, Y. M. et al. A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS. Cell Stem Cell 12, 713–726 (2013). Similarly to reference 51, this study uses a neurotrophin withdrawal stress paradigm to identify kenpaullone as a neuroprotective compound that inhibits HGK.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Braam, S. R. et al. Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes. Stem Cell Res. 4, 107–116 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Liang, P. et al. Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation 127, 1677–1691 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Poduri, A., Evrony, G. D., Cai, X. & Walsh, C. A. Somatic mutation, genomic variation, and neurological disease. Science 341, 1237758 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gore, A. et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63–67 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Theka, I. et al. Rapid generation of functional dopaminergic neurons from human induced pluripotent stem cells through a single-step procedure using cell lineage transcription factors. Stem Cells Transl. Med. 2, 473–479 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Han, D. W. et al. Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell 10, 465–472 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Zwaka, T. P. & Thomson, J. A. Homologous recombination in human embryonic stem cells. Nature Biotech. 21, 319–321 (2003).

    Article  CAS  Google Scholar 

  60. Heaney, J. D., Rettew, A. N. & Bronson, S. K. Tissue-specific expression of a BAC transgene targeted to the Hprt locus in mouse embryonic stem cells. Genomics 83, 1072–1082 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Xue, H. et al. A targeted neuroglial reporter line generated by homologous recombination in human embryonic stem cells. Stem Cells 27, 1836–1846 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Song, H., Chung, S. K. & Xu, Y. Modeling disease in human ESCs using an efficient BAC-based homologous recombination system. Cell Stem Cell 6, 80–89 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Goulburn, A. L. et al. A targeted NKX2.1 human embryonic stem cell reporter line enables identification of human basal forebrain derivatives. Stem Cells 29, 462–473 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Aizawa, E. et al. Efficient and accurate homologous recombination in hESCs and hiPSCs using helper-dependent adenoviral vectors. Mol. Ther. 20, 424–431 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Hockemeyer, D. et al. Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nature Biotech. 27, 851–857 (2009).

    Article  CAS  Google Scholar 

  66. Hockemeyer, D. et al. Genetic engineering of human pluripotent cells using TALE nucleases. Nature Biotech. 29, 731–734 (2011).

    Article  CAS  Google Scholar 

  67. Fu, Y. et al. High-frequency off-target mutagenesis induced by CRISPR–Cas nucleases in human cells. Nature Biotech. 31, 822–826 (2013).

    Article  CAS  Google Scholar 

  68. Ran, F. A. et al. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154, 1380–1389 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Mali, P. et al. CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nature Biotech. 31, 833–838 (2013).

    Article  CAS  Google Scholar 

  70. Ding, Q. et al. Enhanced efficiency of human pluripotent stem cell genome editing through replacing TALENs with CRISPRs. Cell Stem Cell 12, 393–394 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kelly, R. D., Mahmud, A., McKenzie, M., Trounce, I. A. & St John, J. C. Mitochondrial DNA copy number is regulated in a tissue specific manner by DNA methylation of the nuclear-encoded DNA polymerase gamma A. Nucleic Acids Res. 40, 10124–10138 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Van Blerkom, J., Sinclair, J. & Davis, P. Mitochondrial transfer between oocytes: potential applications of mitochondrial donation and the issue of heteroplasmy. Hum. Reprod. 13, 2857–2868 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. Brenner, C. A., Barritt, J. A., Willadsen, S. & Cohen, J. Mitochondrial DNA heteroplasmy after human ooplasmic transplantation. Fertil. Steril. 74, 573–578 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Tachibana, M. et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 153, 1228–1238 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tachibana, M. et al. Towards germline gene therapy of inherited mitochondrial diseases. Nature 493, 627–631 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Kriks, S. et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 480, 547–551 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Reinhardt, P. et al. Derivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling. PLoS ONE 8, e59252 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Koch, P., Opitz, T., Steinbeck, J. A., Ladewig, J. & Brustle, O. A rosette-type, self-renewing human ES cell-derived neural stem cell with potential for in vitro instruction and synaptic integration. Proc. Natl Acad. Sci. USA 106, 3225–3230 (2009).

    Article  PubMed  Google Scholar 

  79. Li, W. et al. Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors. Proc. Natl Acad. Sci. USA 108, 8299–8304 (2011).

    Article  PubMed  Google Scholar 

  80. Cao, N. et al. Highly efficient induction and long-term maintenance of multipotent cardiovascular progenitors from human pluripotent stem cells under defined conditions. Cell Res. 23, 1119–1132 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Cheng, X. et al. Self-renewing endodermal progenitor lines generated from human pluripotent stem cells. Cell Stem Cell 10, 371–384 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hannan, N. R. et al. Generation of multipotent foregut stem cells from human pluripotent stem cells. Stem Cell Rep. 1, 293–306 (2013).

    Article  CAS  Google Scholar 

  83. Mummery, C. L. et al. Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: a methods overview. Circ. Res. 111, 344–358 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Takebe, T. et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499, 481–484 (2013).

    Article  CAS  PubMed  Google Scholar 

  85. Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Eiraku, M. et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472, 51–56 (2011). References 84–86 show proof of principle for organoid generation.

    Article  CAS  PubMed  Google Scholar 

  87. Nakano, T. et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10, 771–785 (2012).

    Article  CAS  PubMed  Google Scholar 

  88. Andrée, B., Bär, A., Haverich, A. & Hilfiker, A. Small intestinal submucosa segments as matrix for tissue engineering: review. Tissue Eng. Part B Rev. 19, 279–291 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Bhise, N. S. et al. Organ-on-a-chip platforms for studying drug delivery systems. J. Control Release http://dx.doi.org/10.1016/j.jconrel.2014.05.004 (2014).

  90. Botta-Orfila, T. et al. Age at onset in LRRK2-associated PD is modified by SNCA variants. J. Mol. Neurosci. 48, 245–247 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Rashid, S. T. et al. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J. Clin. Invest. 120, 3127–3136 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Almeida, S. et al. Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects. Cell Rep. 2, 789–798 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sareen, D. et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci. Transl Med. 5, 208ra149 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Almeida, S. et al. Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol. 126, 385–399 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Donnelly, C. J. et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80, 415–428 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Chen, H. et al. Modeling ALS with iPSCs reveals that mutant SOD1 misregulates neurofilament balance in motor neurons. Cell Stem Cell 14, 796–809 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kiskinis, E. et al. Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1. Cell Stem Cell 14, 781–795 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wainger, B. J. et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 7, 1–11 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Egawa, N. et al. Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci. Transl Med. 4, 145ra104 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Bilican, B. et al. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc. Natl Acad. Sci. USA 109, 5803–5808 (2012).

    Article  PubMed  Google Scholar 

  101. Serio, A. et al. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc. Natl Acad. Sci. USA 110, 4697–4702 (2013).

    Article  PubMed  Google Scholar 

  102. Israel, M. A. et al. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature 482, 216–220 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Mertens, J. et al. APP processing in human pluripotent stem cell-derived neurons is resistant to NSAID-based γ-secretase modulation. Stem Cell Rep. 1, 491–498 (2013).

    Article  CAS  Google Scholar 

  104. Yagi, T. et al. Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum. Mol. Genet. 20, 4530–4539 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Shi, Y. et al. A human stem cell model of early Alzheimer's disease pathology in Down syndrome. Sci. Transl Med. 4, 124ra29 (2012).

    PubMed  PubMed Central  Google Scholar 

  106. Jiang, Y. et al. Derivation and functional analysis of patient-specific induced pluripotent stem cells as an in vitro model of chronic granulomatous disease. Stem Cells 30, 599–611 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Novak, A. et al. Cardiomyocytes generated from CPVTD307H patients are arrhythmogenic in response to β-adrenergic stimulation. J. Cell. Mol. Med. 16, 468–482 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Fatima, A. et al. In vitro modeling of ryanodine receptor 2 dysfunction using human induced pluripotent stem cells. Cell Physiol. Biochem. 28, 579–592 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kujala, K. et al. Cell model of catecholaminergic polymorphic ventricular tachycardia reveals early and delayed afterdepolarizations. PLoS ONE 7, e44660 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhang, X. H. et al. Ca2+ signaling in human induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) from normal and catecholaminergic polymorphic ventricular tachycardia (CPVT)-afflicted subjects. Cell Calcium 54, 57–70 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Jung, C. B. et al. Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia. EMBO Mol. Med. 4, 180–191 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sheridan, S. D. et al. Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. PLoS ONE 6, e26203 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Matsa, E. et al. Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation. Eur. Heart J. 32, 952–962 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lahti, A. L. et al. Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture. Dis. Model. Mech. 5, 220–230 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Bellin, M. et al. Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome. EMBO J. 32, 3161–3175 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Egashira, T. et al. Disease characterization using LQTS-specific induced pluripotent stem cells. Cardiovasc. Res. 95, 419–429 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. Terrenoire, C. et al. Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics. J. Gen. Physiol. 141, 61–72 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Davis, R. P. et al. Cardiomyocytes derived from pluripotent stem cells recapitulate electrophysiological characteristics of an overlap syndrome of cardiac sodium channel disease. Circulation 125, 3079–3091 (2012).

    Article  PubMed  Google Scholar 

  119. Ma, D. et al. Modeling type 3 long QT syndrome with cardiomyocytes derived from patient-specific induced pluripotent stem cells. Int. J. Cardiol 168, 5277–5286 (2013).

    Article  PubMed  Google Scholar 

  120. Quarto, N. et al. Skeletogenic phenotype of human Marfan embryonic stem cells faithfully phenocopied by patient-specific induced-pluripotent stem cells. Proc. Natl Acad. Sci. USA 109, 215–220 (2012).

    Article  PubMed  Google Scholar 

  121. Cooper, O. et al. Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease. Sci. Transl Med. 4, 141ra90 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Orenstein, S. J. et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nature Neurosci. 16, 394–406 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Sanders, L. H. et al. LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: reversal by gene correction. Neurobiol. Dis. 62, 381–386 (2014).

    Article  CAS  PubMed  Google Scholar 

  124. Jiang, H. et al. Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nature Commun. 3, 668 (2012).

    Article  CAS  Google Scholar 

  125. Imaizumi, Y. et al. Mitochondrial dysfunction associated with increased oxidative stress and alpha-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue. Mol. Brain 5, 35 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Seibler, P. et al. Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J. Neurosci. 31, 5970–5976 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Byers, B. et al. SNCA triplication Parkinson's patient's iPSC-derived DA neurons accumulate α-synuclein and are susceptible to oxidative stress. PLoS ONE 6, e26159 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Yagi, T. et al. Establishment of induced pluripotent stem cells from centenarians for neurodegenerative disease research. PLoS ONE 7, e41572 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Huang, H. P. et al. Human Pompe disease-induced pluripotent stem cells for pathogenesis modeling, drug testing and disease marker identification. Hum. Mol. Genet. 20, 4851–4864 (2011).

    Article  CAS  PubMed  Google Scholar 

  130. Suzuki, T. et al. Use of induced pluripotent stem cells to recapitulate pulmonary alveolar proteinosis pathogenesis. Am. J. Respir. Crit. Care Med. 189, 183–193 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Lachmann, N. et al. Gene correction of human induced pluripotent stem cells repairs the cellular phenotype in pulmonary alveolar proteinosis. Am. J. Respir. Crit. Care Med. 189, 167–182 (2014).

    CAS  PubMed  Google Scholar 

  132. Ananiev, G., Williams, E. C., Li, H. & Chang, Q. Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model. PLoS ONE 6, e25255 (2011). References 30, 39–41, 96–98, 123 and 132 show that genetic correction of a mutation that causes a neurodegenerative disease in patients leads to a phenotypic reversion in vitro.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Cheung, A. Y. et al. Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum. Mol. Genet. 20, 2103–2115 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kim, K. Y., Hysolli, E. & Park, I. H. Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome. Proc. Natl Acad. Sci. USA 108, 14169–14174 (2011).

    Article  PubMed  Google Scholar 

  135. Brennand, K. J. et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221–225 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Sareen, D. et al. Inhibition of apoptosis blocks human motor neuron cell death in a stem cell model of spinal muscular atrophy. PLoS ONE 7, e39113 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Chang, T. et al. Brief report: phenotypic rescue of induced pluripotent stem cell-derived motoneurons of a spinal muscular atrophy patient. Stem Cells 29, 2090–2093 (2011).

    Article  CAS  PubMed  Google Scholar 

  138. Pasca, S. P. et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nature Med. 17, 1657–1662 (2011).

    Article  CAS  PubMed  Google Scholar 

  139. Yazawa, M. et al. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471, 230–234 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Krey, J. F. et al. Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nature Neurosci. 16, 201–209 (2013).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank A. Malapetsas for editing and acknowledge support from the Max Planck Society.

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Authors and Affiliations

  1. Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149, Münster, Germany

    Jared L. Sterneckert, Peter Reinhardt & Hans R. Schöler

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  1. Jared L. Sterneckert
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  2. Peter Reinhardt
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  3. Hans R. Schöler
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Correspondence to Hans R. Schöler.

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Competing interests

The authors are inventors on a patent application covering smNPCs, which are discussed in this Review.

PowerPoint slides

Glossary

Self-renewal

The ability to give rise to identical daughter cells by division without losing differentiation potential.

Genetically complex disorders

Disorders with pathology induced by polymorphisms at more than one locus, potentially in combination with at least one environmental factor.

Pluripotent stem cells

(PSCs). Stem cells that can give rise to cells and tissues of all three germ layers (that is, the endoderm, mesoderm and ectoderm), as well as the germ line.

Genome editing

Deliberate and specific modification of the genome, for example, to correct a disease-causing point mutation to the wild-type gene.

Fragile X syndrome

(FXS). A genetic disorder caused by trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR1) gene, which is necessary for normal brain development.

Amyotrophic lateral sclerosis

(ALS). A neurodegenerative disorder caused by selective and progressive loss of motor neurons.

End-stage disease

The final stages of a disease pathology, often just before death.

Pre-implantation genetic diagnosis

(PGD). An assisted reproductive technology used to diagnose a disease-causing mutation in an embryo. Wild-type embryos can then be implanted into the mother for gestation.

Huntington's disease

(HD). A neurodegenerative, autosomal dominant genetic disorder caused by trinucleotide repeat expansions in the huntingtin (HTT) gene, which leads to changes in cognition, personality and motor control.

Sporadic diseases

A disease form in which the patient has no familial history of the disorder and that has no known cause.

Long QT syndrome

A genetic heart disease that leads to prolonged QT intervals and sometimes irregularities in heartbeat that are associated with clinical implications.

Dominant-negative

Pertaining to a mutation in an allele that adversely affects the gene product of the remaining wild-type allele, for example, by dimerization.

Lewy body

An intracellular protein aggregate that consists of various proteins, including α-synuclein, ubiquitin and microtubule-associated protein tau (MAPT); it can be found in Parkinson's disease and Lewy body dementia.

Machado–Joseph disease

(MJD). A rare autosomal dominant genetic disease caused by trinucleotide repeat expansions in the ataxin 3 (ATXN3) gene, which leads to progressive spinocerebellar ataxia.

Mendelian diseases

Diseases caused by a mutation in a single locus with high penetrance.

Gene targeting

A technology that specifically targets one part of the genome for modification.

Tauopathy

A class of neurodegenerative diseases characterized by pathological aggregation and misfolding of microtubule-associated protein tau (MAPT).

Heteroplasmy

The existence of a mixture of different mitochondrial genomes in a single cell; that is, not all copies are identical.

Non-cell-autonomous toxicity

Toxicity in a cell that is caused by factors produced by other cell types, such as the degeneration of motor neurons as a result of factors produced by other non-motor-neuron cells (for example, astrocytes).

Field potential duration

The duration of an extracellular electrical potential produced by cells; it can be recorded by electrodes from cells such as cardiomyocytes and can be correlated with the QT interval of an electrocardiogram.

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Sterneckert, J., Reinhardt, P. & Schöler, H. Investigating human disease using stem cell models. Nat Rev Genet 15, 625–639 (2014). https://doi.org/10.1038/nrg3764

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